tbuckley/cabot-search huggingface dataset:
Expression of mTOR in normal and pathological conditions
Authors: A Marques-Ramos, R Cervantes
Journal: Molecular Cancer (2023)

The mechanistic/mammalian target of rapamycin (mTOR), a protein discovered in 1991, integrates a complex pathway with a key role in maintaining cellular homeostasis. By comprising two functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2, it is a central cellular hub that integrates intra- and extracellular signals of energy, nutrient, and hormone availability, modulating the molecular responses to acquire a homeostatic state through the regulation of anabolic and catabolic processes. Accordingly, dysregulation of mTOR pathway has been implicated in a variety of human diseases. While major advances have been made regarding the regulators and effectors of mTOR signaling pathway, insights into the regulation of mTOR gene expression are beginning to emerge. Here, we present the current available data regarding the mTOR expression regulation at the level of transcription, translation and mRNA stability and systematize the current knowledge about the fluctuations of mTOR expression observed in several diseases, both cancerous and non-cancerous. In addition, we discuss whether mTOR expression changes can be used as a biomarker for diagnosis, disease progression, prognosis and/or response to therapeutics. We believe that our study will contribute for the implementation of new disease biomarkers based on mTOR as it gives an exhaustive perspective about the regulation of mTOR gene expression in both normal and pathological conditions.
Nasal and blood transcriptomic pathways underpinning the clinical response to grass pollen immunotherapy
Authors: Matthew C. Altman, R. Max Segnitz, David Larson, Naresh Doni Jayavelu, Malisa T. Smith, Sana Patel, Guy W. Scadding, Tielin Qin, Srinath Sanda, Esther Steveling, Aarif O. Eifan, Martin Penagos, Mikila R. Jacobson, Rebecca V. Parkin, Mohamed H. Shamji, Alkis Togias, Stephen R. Durham
Journal: Journal of Allergy and Clinical Immunology (2023)
Hepatocellular Carcinoma Diagnosis and Management in 2021: A National Veterans Affairs Quality Improvement Project
Authors: Shari S. Rogal, Tamar H. Taddei, Alexander Monto, Vera Yakovchenko, Heather Patton, Monica Merante, Patrick Spoutz, Linda Chia, Jennifer Yudkevich, Ayse Aytaman, Atoosa Rabiee, Binu V. John, Boris Blechacz, Cindy X. Cai, HoChong Gilles, Anand S. Shah, Heather McCurdy, Puneet Puri, Janice Jou, Khurram Mazhar, Jason A. Dominitz, Jennifer Anwar, Timothy R. Morgan, George N. Ioannou
Journal: Clinical Gastroenterology and Hepatology (2023)
Convergent abnormality in the subgenual anterior cingulate cortex in insomnia disorder: A revisited neuroimaging meta-analysis of 39 studies
Authors: Gerion M. Reimann, Vincent Küppers, Julia A. Camilleri, Felix Hoffstaedter, Robert Langner, Angela R. Laird, Peter T. Fox, Kai Spiegelhalder, Simon B. Eickhoff, Masoud Tahmasian
Journal: Sleep Medicine Reviews (2023)
Angiogenesis, hemocompatibility and bactericidal effect of bioactive natural polymer‐based bilayer adhesive skin substitute for infected burned wound healing
Authors: Mina Shahriari-Khalaji, Mamoona Sattar, Ran Cao, Meifang Zhu
Journal: Bioactive Materials (2023)

Thermal wounds are complex and lethal with irregular shapes, risk of infection, slow healing, and large surface area. The mortality rate in patients with infected burns is twice that of non-infected burns. Developing multifunctional skin substitutes to augment the healing rate of infected burns is vital. Herein, we 3D printed a hydrogel scaffold comprising carboxymethyl chitosan (CMCs) and oxidized alginate grafted catechol (O-AlgCat) on a hydrophobic electrospun layer, forming a bilayer skin substitute (BSS). The functional layer (FL) was fabricated by physiochemical crosslinking to ensure favorable biodegradability. The gallium-containing hydrophobic electrospun layer or backing layer (BL) could mimic the epidermis of skin, avoiding fluid penetration and offering antibacterial activity. 3D printed FL contains catechol, gallium, and biologically active platelet rich fibrin (PRF) to adhere to both tissue and BL, show antibacterial activity, encourage angiogenesis, cell growth, and migration. The fabricated bioactive BSS exhibited noticeable adhesive properties (P ≤ 0.05), significant antibacterial activity (P ≤ 0.05), faster clot formation, and the potential to promote proliferation (P ≤ 0.05) and migration (P ≤ 0.05) of L929 cells. Furthermore, the angiogenesis was significantly higher (P ≤ 0.05) when evaluated in vivo and in ovo. The BSS-covered wounds healed faster due to low inflammation and high collagen density. Based on the obtained results, the fabricated bioactive BSS could be an effective treatment for infected burn wounds.
Association of Artificial Tears with Ocular and Systemic Infection: Carbapenem-resistant Pseudomonas aeruginosa (VIM-GES-CRPA) Outbreak
Authors: Frida Velcani, Irene C. Kuo, Robert M.Q. Shanks, James Chodosh, Prashant Garg, Guillermo Amescua, Michael E. Zegans
Journal: Ophthalmology (2023)
Lichen sclerosus: evidence that immunological changes occur at all levels of the skin
Authors: None Farrell, None Marren, None Dean, None Wojnarowska
Journal: British Journal of Dermatology (1999)

An immunohistochemical approach was used to characterize the inflammatory infiltrate in vulval lichen sclerosus, using monoclonal antibodies to CD3, CD4, CD8, CD68 and HLA‐DR. Significant numbers of CD4 + and CD8 + lymphocytes were observed in the dermal band of inflammatory cells in approximately equal proportions. Less numerous CD4 + and CD8 + lymphocytes also occurred adjacent to the dermoepidermal junction and occasionally in the lower epidermis. Increased numbers of cells staining with the monocyte/macrophage marker CD68 were also present in the band of inflammatory cells as well as being scattered diffusely throughout the sclerotic region. Expression of HLA‐DR in the lichen sclerosus specimens was increased within the inflammatory infiltrate and around blood vessels in the dermis. All the vulval lichen sclerosus specimens also demonstrated some HLA‐DR expression around the keratinocytes, suggesting that these keratinocytes might be involved in antigen presentation. We also studied the expression of CD44 and its isoforms 3G5 (marker of V3), 8G5 (marker of V6), 3D2 (marker of V4/5) and IE8 (marker of V8/9). CD44 has been proposed to play a part in lymphocyte homing, cell–matrix interaction (particularly with hyaluronic acid), lymphocyte activation and malignant progression of certain tumours. The epidermis of the lichen sclerosus specimens appeared to demonstrate a greater intensity of staining with the pan‐CD44 marker F10‐44, and reduced staining with 3G5, 3D2 and IE8 compared with normal skin. Like normal skin, the dermis of the lichen sclerosus specimens did not demonstrate staining with 3G5, 3D2, 8G5 or 1E8, but did show staining with F10‐44. However, the pattern of the dermal staining with F10‐44 reflected the position of the inflammatory infiltrate and was sparse in the five sections where there was a prominent sclerotic zone, but increased in the three sections where there was a prominent band of inflammation cells. Our results demonstrate evidence of immunological changes at all levels of skin involved by lichen sclerosus, including the epidermis.
hnRNPH2 gain-of-function mutations reveal therapeutic strategies and a role for RNA granules in neurodevelopmental disorders
Authors: Benjamin A. Kelvington, Ted Abel
Journal: Journal of Clinical Investigation (2023)

hnRNPH2-related neurodevelopmental disorder (NDD) is caused by mutations in the HNRNPH2 gene and is associated with substantial challenges, including developmental delay, intellectual disability, growth delay, and epilepsy. There is currently no therapeutic intervention available to those with hnRNPH2-related NDD that addresses its underlying mechanisms. In this issue of the JCI, Korff et al. studied specific gain-of-function mutations associated with hnRNPH2-related NDD, with the help of mouse models that recapitulate key features of the condition in humans. Their work paves the way for therapeutic approaches that aim to reduce the expression of mutant hnRNPH2 and highlights a role for disrupted RNA granules in neurodevelopmental and neurodegenerative disorders.
Inhibition of DPAGT1 suppresses HER2 shedding and trastuzumab resistance in human breast cancer
Authors: Muwen Yang, None Li, Lingzhi Kong, Shumei Huang, Lixin He, Pian Liu, Shuang Mo, Xiuqing Lu, Xi Lin, Yunyun Xiao, Dongni Shi, Xinjian Huang, Boyu Chen, Xiangfu Chen, Ying Ouyang, None Li, Chuyong Lin, Libing Song
Journal: Journal of Clinical Investigation (2023)

Human epidermal growth factor receptor 2-targeted (HER2-targeted) therapy is the mainstay of treatment for HER2+ breast cancer. However, the proteolytic cleavage of HER2, or HER2 shedding, induces the release of the target epitope at the ectodomain (ECD) and the generation of a constitutively active intracellular fragment (p95HER2), impeding the effectiveness of anti-HER2 therapy. Therefore, identifying key regulators in HER2 shedding might provide promising targetable vulnerabilities against resistance. In the current study, we found that upregulation of dolichyl-phosphate N-acetylglucosaminyltransferase (DPAGT1) sustained high-level HER2 shedding to confer trastuzumab resistance, which was associated with poor clinical outcomes. Upon trastuzumab treatment, the membrane-bound DPAGT1 protein was endocytosed via the caveolae pathway and retrogradely transported to the ER, where DPAGT1 induced N-glycosylation of the sheddase - ADAM metallopeptidase domain 10 (ADAM10) - to ensure its expression, maturation, and activation. N-glycosylation of ADAM10 at N267 protected itself from ER-associated protein degradation and was essential for DPAGT1-mediated HER2 shedding and trastuzumab resistance. Importantly, inhibition of DPAGT1 with tunicamycin acted synergistically with trastuzumab treatment to block HER2 signaling and reverse resistance. These findings reveal a prominent mechanism for HER2 shedding and suggest that targeting DPAGT1 might be a promising strategy against trastuzumab-resistant breast cancer.
Preserving mitochondria to treat hypertrophic cardiomyopathy: From rare mitochondrial DNA mutation to heart failure therapy?
Authors: Abhinav Diwan
Journal: Journal of Clinical Investigation (2023)

Hypertrophic cardiomyopathy and pathological cardiac hypertrophy are characterized by mitochondrial structural and functional abnormalities. In this issue of the JCI, Zhuang et al. discovered 1-deoxynojirimycin (DNJ) through a screen of mitochondrially targeted compounds. The authors described the effects of DNJ in restoring mitochondria and preventing cardiac myocyte hypertrophy in cellular models carrying a mutant mitochondrial gene, MT-RNR2, which is causally implicated in familial hypertrophic cardiomyopathy. DNJ worked via stabilization of the mitochondrial inner-membrane GTPase OPA1 and other, hitherto unknown, mechanisms to preserve mitochondrial crista and respiratory chain components. The discovery is likely to spur development of a class of therapeutics that restore mitochondrial health to prevent cardiomyopathy and heart failure.
Differential roles of regulatory T cells in acute respiratory infections
Authors: Milica Jovisic, Nurbek Mambetsariev, Benjamin D. Singer, Luisa Morales-Nebreda
Journal: Journal of Clinical Investigation (2023)

Acute respiratory infections trigger an inflammatory immune response with the goal of pathogen clearance; however, overexuberant inflammation causes tissue damage and impairs pulmonary function. CD4+FOXP3+ regulatory T cells (Tregs) interact with cells of both the innate and the adaptive immune system to limit acute pulmonary inflammation and promote its resolution. Tregs also provide tissue protection and coordinate lung tissue repair, facilitating a return to homeostatic pulmonary function. Here, we review Treg-mediated modulation of the host response to respiratory pathogens, focusing on mechanisms underlying how Tregs promote resolution of inflammation and repair of acute lung injury. We also discuss potential strategies to harness and optimize Tregs as a cellular therapy for patients with severe acute respiratory infection and discuss open questions in the field.
Staring at the onco-exaptation: the two-faced medley of an ancient retrovirus, HERVH
Authors: Manvendra Singh, Aleksandra M. Kondraskhina, Laurence D. Hurst, Zsuzsanna Izsvák
Journal: Journal of Clinical Investigation (2023)

Cell senescence suppresses tumors by arresting cells at risk of becoming malignant. However, this process in turn can affect the microenvironment, leading to acquisition of a senescence-associated secretory phenotype (SASP) that renders senescent cells proinflammatory and results in tumor progression. But how is SASP controlled? In this issue of the JCI, Attig and Pape et al. describe the role of chimeric calbindin 1 (CALB1) transcripts, which are driven by an upstream human endogenous retrovirus subfamily H (HERVH) element. The authors propose that in lung squamous cell carcinoma (LUSC), HERVH-driven isoforms of calbindin (HERVH-CALB1) counteract SASP. As an alternative promoter, HERVH drove calbindin isoforms that prevented cancer cell senescence and associated inflammation, which was associated with better patient survival. We comment on the similarities between HERVH-CALB1-related cellular fitness in cancer and early embryogenesis and discuss the potential benefits of HERVH-driven chimeric transcripts.
A murine model of hnRNPH2-related neurodevelopmental disorder reveals a mechanism for genetic compensation by Hnrnph1
Authors: Ane Korff, Xiaojing Yang, Kevin O’Donovan, Abner Gonzalez, Brett J.W. Teubner, Haruko Nakamura, James Messing, Fen Yang, Alexandre F. Carisey, Yong-Dong Wang, Tushar Patni, Heather Sheppard, Stanislav S. Zakharenko, Yuh Min Chook, J. Paul Taylor, Hong Joo Kim
Journal: Journal of Clinical Investigation (2023)

Mutations in HNRNPH2 cause an X-linked neurodevelopmental disorder with features that include developmental delay, motor function deficits, and seizures. More than 90% of patients with hnRNPH2 have a missense mutation within or adjacent to the nuclear localization signal (NLS) of hnRNPH2. Here, we report that hnRNPH2 NLS mutations caused reduced interaction with the nuclear transport receptor Kapβ2 and resulted in modest cytoplasmic accumulation of hnRNPH2. We generated 2 knockin mouse models with human-equivalent mutations in Hnrnph2 as well as Hnrnph2-KO mice. Knockin mice recapitulated clinical features of the human disorder, including reduced survival in male mice, impaired motor and cognitive functions, and increased susceptibility to audiogenic seizures. In contrast, 2 independent lines of Hnrnph2-KO mice showed no detectable phenotypes. Notably, KO mice had upregulated expression of Hnrnph1, a paralog of Hnrnph2, whereas knockin mice failed to upregulate Hnrnph1. Thus, genetic compensation by Hnrnph1 may counteract the loss of hnRNPH2. These findings suggest that HNRNPH2-related disorder may be driven by a toxic gain of function or a complex loss of HNRNPH2 function with impaired compensation by HNRNPH1. The knockin mice described here are an important resource for preclinical studies to assess the therapeutic benefit of gene replacement or knockdown of mutant hnRNPH2.
Antigen-presenting aged neutrophils induce CD4+ T cells to exacerbate inflammation in sepsis
Authors: Hui Jin, Monowar Aziz, Atsushi Murao, Molly Kobritz, Andrew J. Shih, Robert P. Adelson, Max Brenner, Ping Wang
Journal: Journal of Clinical Investigation (2023)

Extracellular cold-inducible RNA-binding protein (eCIRP) is a key mediator of severity and mortality in sepsis. We found that stimulation of mouse bone marrow–derived neutrophils (BMDNs) with eCIRP generated a distinct neutrophil subpopulation, characterized by cell surface markers of both antigen-presenting cells and aged neutrophils as well as expression of IL-12, which we named antigen-presenting aged neutrophils (APANs). The frequency of APANs was significantly increased in the blood, spleen, and lungs of WT mice subjected to cecal ligation and puncture–induced sepsis but not in CIRP–/– mice. Patients with sepsis had a significant increase in circulating APAN counts compared with healthy individuals. Compared with non–APAN-transfered mice, APAN-transferred septic mice had increased serum levels of injury and inflammatory markers, exacerbated acute lung injury (ALI), and worsened survival. APANs and CD4+ T cells colocalized in the spleen, suggesting an immune interaction between these cells. APANs cocultured with CD4+ T cells significantly induced the release of IFN-γ via IL-12. BMDNs stimulated with eCIRP and IFN-γ underwent hyper-NETosis. Stimulating human peripheral blood neutrophils with eCIRP also induced APANs, and stimulating human neutrophils with eCIRP and IFN-γ caused hyper-NETosis. Thus, eCIRP released during sepsis induced APANs to aggravate ALI and worsen the survival of septic animals via CD4+ T cell activation, Th1 polarization, and IFN-γ–mediated hyper-NETosis.
The lung mesenchyme in development, regeneration, and fibrosis
Authors: Elie El Agha, Victor J. Thannickal
Journal: Journal of Clinical Investigation (2023)

Mesenchymal cells are uniquely located at the interface between the epithelial lining and the stroma, allowing them to act as a signaling hub among diverse cellular compartments of the lung. During embryonic and postnatal lung development, mesenchyme-derived signals instruct epithelial budding, branching morphogenesis, and subsequent structural and functional maturation. Later during adult life, the mesenchyme plays divergent roles wherein its balanced activation promotes epithelial repair after injury while its aberrant activation can lead to pathological remodeling and fibrosis that are associated with multiple chronic pulmonary diseases, including bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. In this Review, we discuss the involvement of the lung mesenchyme in various morphogenic, neomorphogenic, and dysmorphogenic aspects of lung biology and health, with special emphasis on lung fibroblast subsets and smooth muscle cells, intercellular communication, and intrinsic mesenchymal mechanisms that drive such physiological and pathophysiological events throughout development, homeostasis, injury repair, regeneration, and aging.
RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia
Authors: Nathalie Launay, Montserrat Ruiz, Laura Planas-Serra, Edgard Verdura, Agustí Rodríguez-Palmero, Agatha Schlüter, Leire Goicoechea, Cristina Guilera, Josefina Casas, Felix Campelo, Emmanuelle Jouanguy, Jean-Laurent Casanova, Odile Boespflug-Tanguy, Maria Vazquez Cancela, Luis González Gutiérrez-Solana, Carlos Casasnovas, Estela Area-Gomez, Aurora Pujol
Journal: Journal of Clinical Investigation (2023)

The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset episodic acute liver failure (ALF). Here, we describe 3 individuals from 2 unrelated families with novel biallelic RINT1 loss-of-function variants who presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, and dysmorphic features, broadening the previously described phenotype. Our functional and lipidomic analyses provided evidence that pathogenic RINT1 variants induce defective lipid-droplet biogenesis and profound lipid abnormalities in fibroblasts and plasma that impact both neutral lipid and phospholipid metabolism, including decreased triglycerides and diglycerides, phosphatidylcholine/phosphatidylserine ratios, and inhibited Lands cycle. Further, RINT1 mutations induced intracellular ROS production and reduced ATP synthesis, affecting mitochondria with membrane depolarization, aberrant cristae ultrastructure, and increased fission. Altogether, our results highlighted the pivotal role of RINT1 in lipid metabolism and mitochondria function, with a profound effect in central nervous system development.
Connections between ApoE, sleep, and Aβ and tau pathologies in Alzheimer’s disease
Authors: Katherine R. Sadleir, Robert Vassar
Journal: Journal of Clinical Investigation (2023)

In this issue of the JCI, Wang and colleagues investigate the relationship between sleep disturbances, an environmental risk factor for Alzheimer's disease (AD), and the apolipoprotein 4 (APOEε4) allele, a strong genetic risk factor for AD. The authors subjected an amyloid mouse model expressing human APOE3 or APOE4, with and without human AD-tau injection, to sleep deprivation and observed that amyloid and tau pathologies were worsened in the presence of APOE4. Moreover, decreased microglial clustering and increased dystrophic neurites around plaques were observed in sleep-deprived APOE4 mice. In addition, aquaporin 4, important for clearing amyloid-β through the glymphatic system, was reduced and less polarized to astrocytic endfeet. These APOE4-induced changes caused alterations in sleep behavior during recovery from sleep deprivation, suggesting a feed-forward cycle of sleep disturbance and increased AD pathology that can further disrupt sleep in the presence of APOE4.
Miriplatin-loaded liposome, as a novel mitophagy inducer, suppresses pancreatic cancer proliferation through blocking POLG and TFAM-mediated mtDNA replication
Authors: Xiaowei Wang, Mengyan Wang, Meilian Cai, Rongguang Shao, Guimin Xia, Wuli Zhao
Journal: Acta Pharmaceutica Sinica B (2023)

Pancreatic cancer is a more aggressive and refractory malignancy. Resistance and toxicity limit drug efficacy. Herein, we report a lower toxic and higher effective miriplatin (MPt)-loaded liposome, LMPt, exhibiting totally different anti-cancer mechanism from previously reported platinum agents. Both in gemcitabine (GEM)-resistant/sensitive (GEM-R/S) pancreatic cancer cells, LMPt exhibits prominent anti-cancer activity, led by faster cellular entry-induced larger accumulation of MPt. The level of caveolin-1 (Cav-1) determines entry rate and switch of entry pathways of LMPt, indicating a novel role of Cav-1 in nanoparticle entry. After endosome-lysosome processing, in unchanged metabolite, MPt is released and targets mitochondria to enhance binding of mitochondria protease LONP1 with POLG and TFAM, to degrade POLG and TFAM. Then, via PINK1-Parkin axis, mitophagy is induced by POLG and TFAM degradation-initiated mitochondrial DNA (mtDNA) replication blocking. Additionally, POLG and TFAM are identified as novel prognostic markers of pancreatic cancer, and mtDNA replication-induced mitophagy blocking mediates their pro-cancer activity. Our findings reveal that the target of this liposomal platinum agent is mitochondria but not DNA (target of most platinum agents), and totally distinct mechanism of MPt and other formulations of MPt. Self-assembly offers LMPt special efficacy and mechanisms. Prominent action and characteristic mechanism make LMPt a promising cancer candidate.